This invention relates to certain 2,4-substituted pyrrolidine derivatives that are CCR-3 receptor antagonists, pharmaceutical compositions containing them, methods for their use and methods for preparing these compounds.
Tissue eosinophilia is a feature of a number of pathological conditions such as asthma, rhinitis, eczema and parasitic infections ((see Bousquet, J. et al. N. Eng. J. Med. 323: 1033-1039 (1990) and Kay, A. B. and Corrigan, C. J. Br. Med. Bull. 48:51-64 (1992)). In asthma, eosinophil accumulation and activation are associated with damage to bronchial epithelium and hyperresponsiveness to constrictor mediators. Chemokines such as RANTES, eotaxin and MCP-3 are known to activate eosinophils ((see Baggiolini, M. and Dahinden, C. A. Immunol. Today. 15:127-133 (1994), Rot, A. M. et al. J. Exp. Med. 176, 1489-1495 (1992) and Ponath, P. D. et al. J. Clin. Invest., Vol. 97, #3, 604-612 (1996)). However, unlike RANTES and MCP-3 which also induce the migration of other leukocyte cell types, eotaxin is selectively chemotactic for eosinophils ((see Griffith-Johnson, D. A et al. Biochem. Biophy. Res. Commun. 197:1167 (1993) and Jose, P. J. et al. Biochem. Biophy. Res. Commun. 207, 788 (1994)). Specific eosinophil accumulation was observed at the site of administration of eotaxin whether by intradermal or intraperitoneal injection or aerosol inhalation ((see Griffith-Johnson, D. A et al. Biochem. Biophy. Res. Commun. 197:1167 (1993); Jose, P. J. et al. J. Exp. Med. 179, 881-887 (1994); Rothenberg, M. E. et al. J. Exp. Med. 181, 1211 (1995) and Ponath. P. D. J. Clin. Invest., Vol. 97, #3, 604-612 (1996)).
Glucocorticoids such as dexamethasone, methprednisolone and hydrocortisone have been used for treating many eosinophil-related disorders, including bronchial asthma (R. P. Schleimer et. al., Am. Rev. Respir. Dis., 141, 559 (1990)). The glucocorticoids are believed to inhibit IL-5, IL-3 mediated eosinophil survival in these diseases. However, prolonged use of glucocorticoids can lead to side effects such as glaucoma, osteoporosis and growth retardation in the patients (see Hanania N. A et al., J. Allergy and Clin. Immunol., Vol. 96, 571-579 (1995) and Saha M. T. et al, Acta Paediatrica, Vol. 86, #2, 138-142 (1997)). It is therefore desirable to have an alternative means of treating eosinophil related diseases without incurring these undesirable side effects.
Recently, the CCR-3 receptor was identified as a major chemokine receptor that eosinophils use for their response to eotaxin, RANTES and MCP-3. When transfected into a murine pre-xcex2 lymphoma line, CCR-3 bound eotaxin, RANTES and MCP-3 and conferred chemotactic responses on these cells to eotaxin, RANTES and MCP-3 (see Ponath. P. D. et al. J. Exp. Med. 183, 2437-2448 (1996)). The CCR-3 receptor is expressed on the surface of eosinophils, T-cells (subtype Th-2), basophils and mast cells and is highly selective for eotaxin. Studies have shown that pretreatment of eosinophils with an anti-CCR-3 mAb completely inhibits eosinophil chemotaxis to eotaxin, RANTES and MCP-3 (see Heath H. et al. J. Clin. Invest., Vol. 99, #2, 178-184 (1997)). Applicants"" co-pending U.S. patent application Ser. Nos. 09/134,013, issued as U.S. Pat. No. 6,323,223 filed Aug. 14, 1998 and WO 00/31032 discloses CCR-3 antagonists that inhibit eosinophilic recruitment by chemokine such as eotaxin. Therefore, blocking the ability of the CCR-3 receptor to bind RANTES, MCP-3 and eotaxin and thereby preventing the recruitment of eosinophils should provide for the treatment of eosinophil-mediated inflammatory diseases.
The present invention concerns novel pyrrolidine derivatives which are capable of inhibiting the binding of eotaxin to the CCR-3 receptor and thereby provide a means of combating eosinophil induced diseases, such as asthma.
In a first aspect, this invention provides a compound of Formula (I): 
wherein:
R1 is hydrogen, alkyl, acyl, heteroalkyl, xe2x80x94CONR3R4 (where R3 and R4 are independently hydrogen or alkyl), xe2x80x94COOR5 (where R5 is hydrogen, alkyl or heteroalkyl), or xe2x80x94SO2R6 where R6 is alkyl;
alk1 is an alkylene chain of 1 to 6 carbon atoms;
X is xe2x80x94NHCOxe2x80x94 or xe2x80x94CONHxe2x80x94;
Y is an alkylene chain of 1 to 3 carbon atoms or an alkylene chain of 2 or 3 carbon atoms wherein one of the carbon atoms is replaced by a heteroatom selected from the group consisting of xe2x80x94Oxe2x80x94, xe2x80x94NRbxe2x80x94 [where Rb is hydrogen, alkyl, acyl, xe2x80x94CONR7R8 (where R7 and R8 are independently hydrogen or alkyl), xe2x80x94COOR9 (where R9 is hydrogen, alkyl or heteroalkyl), aryl, or aralkyl)] and xe2x80x94S(O)nxe2x80x94 wherein n is 0 to 2;
Ar1 is a heteroaryl group or phenyl group wherein the heteroaryl or phenyl group is substituted, in addition to the Ar2 group, with a substituent selected from the group consisting of hydrogen, halo, alkyl, alkoxy, nitro, amido, aminosulfonyl and sulfonylamino;
Ar2 is aryl;
alk2 is an alkylene chain of 1 to 6 carbon atoms wherein one of the carbon atoms is optionally replaced by xe2x80x94COxe2x80x94, xe2x80x94NRCxe2x80x94 [where Rc is hydrogen, alkyl, acyl, xe2x80x94CONR10R11 (where R10 and R11 are independently hydrogen or alkyl), xe2x80x94COOR12 (where R12 is hydrogen, alkyl or heteroalkyl), aryl, or aralkyl)] or xe2x80x94S(O)n1xe2x80x94 wherein n1 is 0 to 2;
Ar3 is cycloalkyl, aryl or heteroaryl; or
a pharmaceutically acceptable salts thereof.
In a second aspect, this invention provides a pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula (I) or it""s pharmaceutically acceptable salt and a pharmaceutically acceptable excipient.
In a third aspect, this invention provides a method of treatment of a disease in a mammal treatable by administration of a CCR-3 receptor antagonist, comprising administration of a pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula (I) or it""s pharmaceutically acceptable salt and a pharmaceutically acceptable excipient. The disease states include respiratory diseases such as asthma.
In a fourth aspect, this invention provides a process for preparing compounds of Formula (I).
In a fifth aspect, this invention provides the use of a compound of Formula (I) or it""s pharmaceutically salt in the preparation of medicament for the treatment of a disease mediated by a CCR-3 receptor. The disease states include respiratory diseases such as asthma.
Unless otherwise stated, the following terms used in the specification and claims have the meanings given below:
xe2x80x9cAlkylxe2x80x9d means a linear saturated monovalent hydrocarbon radical of one to six carbon atoms or a branched saturated monovalent hydrocarbon radical of three to six carbon atoms, e.g., methyl, ethyl, propyl, 2-propyl, n-butyl, iso-butyl, tert-butyl, n-pentyl, 2-, 3-, methylbutyl, neo-pentyl, and the like.
xe2x80x9cAlkylenexe2x80x9d means a linear saturated divalent hydrocarbon radical of one to six carbon atoms or a branched saturated divalent hydrocarbon radical of three to six carbon atoms, e.g., methylene, (2-propyl)methylene, ethylene, methyethylene, (2-propyl)ethylene, propylene, 1- or 2-methylpropylene, 1- or 2-ethylpropylene, pentylene, and the like.
xe2x80x9cAcylxe2x80x9d means a radical xe2x80x94C(O)R where R is alkyl, haloalkyl, alkyl substituted with carboxy, alkoxycarbonyl, heterocycle, or aryloxycarbonyl, aryl, aralkyl, heteroaryl, or heteroaralkyl, e.g., acetyl, trifluoroacetyl, xe2x80x94C(O)CH2CO2H, xe2x80x94C(O)xe2x80x94CH2xe2x80x94CO2CH3, benzoyl, thenoyl, and the like.
xe2x80x9cHaloxe2x80x9d means fluoro, chloro, bromo or iodo, preferably fluoro and chloro.
xe2x80x9cHaloalkylxe2x80x9d means alkyl substituted with one or more same or different halo atoms, e.g., xe2x80x94CH2Cl, xe2x80x94CF3, xe2x80x94CH2CF3, xe2x80x94CH2CCl3, and the like.
xe2x80x9cMonoalkylaminoxe2x80x9d means a radical xe2x80x94NHR where R is alkyl, e.g., methylamino, ethylamino, (1-methylethyl)amino, and the like.
xe2x80x9cDialkylaminoxe2x80x9d means a radical xe2x80x94NRRxe2x80x2 where R and Rxe2x80x2 are independently alkyl. Representative examples include, but are not limited to, dimethylamino, methylethylamino, di(1-methylethyl)amino, and the like.
xe2x80x9cSulfonylaminoxe2x80x9d means a radical xe2x80x94NHSO2R where R is hydrogen or alkyl. Representative examples include, but are not limited to, xe2x80x94NH2SO2CH3, and the like.
xe2x80x9cAminosulfonylxe2x80x9d means a radical xe2x80x94SO2NHR where R is alkyl. Representative examples include, but are not limited to, xe2x80x94SO2NH2, xe2x80x94SO2NHCH3, and the like.
xe2x80x9cAlkylsulfonylxe2x80x9d means a radical xe2x80x94SO2R where R is alkyl. Representative examples include, but are not limited to, methylsulfonyl, ethylsulfonyl, and the like.
xe2x80x9cArylxe2x80x9d means a monovalent monocyclic or bicyclic aromatic hydrocarbon radical of 6 to 10 ring atoms. The aryl ring may be optionally substituted independently with one or more substituents, preferably one, two or three substituents selected from alkyl, haloalkyl, alkylthio, alkoxy, halo, cyano, nitro, amino, hydroxylamino, hydroxy, alkylsulfonyl, sulfonylamino, aminosulfonyl, xe2x80x94NRxe2x80x2Rxe2x80x3 (where Rxe2x80x2 is hydrogen or alkyl and Rxe2x80x3 is hydrogen, alkyl, acyl, alkylsulfonyl) and xe2x80x94COOR (where R is hydrogen or alkyl). More specifically the term aryl includes, but is not limited to, phenyl, 1-naphthyl, 2-naphthyl and derivatives thereof such as 2,3-dichlorophenyl, 3,4-dichlorophenyl, methoxyphenyl, 2,3-dimethoxyphenyl, 3,4-dimethoxyphenyl, and the like.
xe2x80x9cHeteroarylxe2x80x9d means a monovalent monocyclic or bicyclic aromatic radical of 5 to 10 ring atoms containing one, two, or three ring heteroatoms selected from N, O, or S, the remaining ring atoms being C. The aromatic radical is optionally fused to a phenyl and optionally substituted with one or two substituents from alkyl, haloalkyl, alkoxy, halo, cyano, nitro, amino, monoalkylamino, dialkylamino, hydroxy and xe2x80x94COOR (where R is hydrogen or alkyl). More specifically the term heteroaryl includes, but is not limited to pyridyl, pyrrolyl, thiophene, pyrazolyl, thiazolyl, imidazolyl, pyrimidinyl, thiadiazolyl, indolyl, carbazolyl, azaindolyl, benzofuranyl, benzimidazolyl, benzthiazolyl, quinoxalinyl, benzotriazolyl, benzisoxazolyl, purinyl, quinolinyl, isoquinolinyl, benzopyranyl, and derivatives thereof.
xe2x80x9cHeterocyclexe2x80x9d or xe2x80x9cHeterocyclylxe2x80x9d means a saturated or unsaturated cyclic radical of 3 to 8 ring atoms in which one or two ring atoms are heteroatoms selected from N, O, or S(O)n (where n is an integer from 0 to 2), the remaining ring atoms being C, where one or two C atoms may optionally be replaced by a carbonyl group. The heterocyclo ring may be optionally substituted independently with one, two or three substituents selected from alkyl, haloalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, halo, cyano, amino, monoalkylamino, dialkylamino, xe2x80x94COOR (where R is hydrogen or alkyl), or xe2x80x94XR (where X is O and R is hydrogen or alkyl. Representative examples include, but are not limited to, tetrahydropyranyl, piperidino, piperazino, pyrrolidino, and the like.
xe2x80x9cHeteroalkylxe2x80x9d means an alkyl radical as defined above, carrying a substituent containing a heteroatom selected from N, O, S(O)n where n is an integer from 0 to 2. Representative substituents include xe2x80x94NRaRb, xe2x80x94ORa or xe2x80x94S(O)nRc, wherein n is an integer from 0 to 2, Ra is hydrogen, alkyl, haloalkyl, or xe2x80x94COR (where R is alkyl, hydroxy, or alkoxy), Rb is hydrogen or alkyl and Rc is hydrogen, alkyl, amino, monoalkylamino, or dialkylamino. Representative examples include, but are not limited to 2-methoxyethyl, hydroxymethyl, methoxymethyl, 2-hydroxyethyl, 3-hydroxypropyl, -aminoethyl, 2-dimethylaminoethyl, and the like.
xe2x80x9cHydroxyalkylxe2x80x9d means a linear monovalent hydrocarbon radical of two to six carbon atoms or a branched monovalent hydrocarbon radical of three or six carbons substituted with one or two hydroxy groups, provided that if two hydroxy groups are present they are not both on the same carbon atom. Representative examples include, but are not limited to, 2-hydroxyethyl, 2-hydroxypropyl, 3-hydroxypropyl, 1-(hydroxymethyl)-2-methylpropyl, 2-hydroxybutyl, 3-hydroxybutyl, 4-hydroxybutyl, 2,3-dihydroxypropyl, 1-(hydroxymethyl)-2-hydroxyethyl, 2,3-dihydroxybutyl, 3,4-dihydroxybutyl and 2-(hydroxymethyl)-3-hydroxypropyl, preferably 2-hydroxyethyl, 2,3-dihydroxypropyl, and 1-(hydroxymethyl)-2-hydroxyethyl. Hydroxyalkyl is a subset of heteroalkyl group.
xe2x80x9cAralkylxe2x80x9d means a radical xe2x80x94RaRb where Ra is an alkylene group and Rb is an aryl group as defined above e.g., benzyl, phenylethyl, 3-(3-chlorophenyl)-2-methylpentyl, and the like.
xe2x80x9cAlkoxyxe2x80x9d means a radical xe2x80x94OR where R is an alkyl, respectively as defined above e.g., methoxy, ethoxy, propoxy, and the like.
xe2x80x9cOptionalxe2x80x9d or xe2x80x9coptionallyxe2x80x9d means that the subsequently described event or circumstance may but need not occur, and that the description includes instances where the event or circumstance occurs and instances in which it does not. For example, xe2x80x9cheterocyclo group optionally mono- or di-substituted with an alkyl groupxe2x80x9d means that the alkyl may but need not be present, and the description includes situations where the heterocyclo group is mono- or disubstituted with an alkyl group and situations where the heterocyclo group is not substituted with the alkyl group.
xe2x80x9cAmino-protecting groupxe2x80x9d refers to those organic groups intended to protect nitrogen atoms against undesirable reactions during synthetic procedures e.g., benzyl, benzyloxycarbonyl (CBZ), t-butoxycarbonyl (BOC), trifluoroacetyl, and the like.
Compounds that have the same molecular formula but differ in the nature or sequence of bonding of their atoms or the arrangement of their atoms in space are termed xe2x80x9cisomersxe2x80x9d. Isomers that differ in the arrangement of their atoms in space are termed xe2x80x9cstereoisomersxe2x80x9d. Stereoisomers that are not mirror images of one another are termed xe2x80x9cdiastereomersxe2x80x9d and those that are non-superimposable mirror images of each other are termed xe2x80x9cenantiomersxe2x80x9d. When a compound has an asymmetric center, for example, if a carbon atom is bonded to four different groups, a pair of enantiomers is possible. An enantiomer can be characterized by the absolute configuration of its asymmetric center and is described by the R- and S-sequencing rules of Cahn and Prelog, or by the manner in which the molecule rotates the plane of polarized light and designated as dextrorotatory or levorotatory (i.e., as (+) or (xe2x88x92)-isomers respectively). A chiral compound can exist as either individual enantiomer or as a mixture thereof. A mixture containing equal proportions of the enantiomers is called a xe2x80x9cracemic mixturexe2x80x9d.
The compounds of this invention may possess one or more asymmetric centers; such compounds can therefore be produced as individual (R)- or (S)-stereoisomers or as mixtures thereof. For example, if the R1 substituent in a compound of Formula (I) is alkyl, then the carbon to which it is attached is an asymmetric center and the compound of Formula (I) can exist as an (R)- or (S)-stereoisomer. Unless indicated otherwise, the description or naming of a particular compound in the specification and claims is intended to include both individual enantiomers and mixtures, racemic or otherwise, thereof. The methods for the determination of stereochemistry and the separation of stereoisomers are well-known in the art (see discussion in Chapter 4 of xe2x80x9cAdvanced Organic Chemistryxe2x80x9d, 4th edition J. March, John Wiley and Sons, New York, 1992).
A xe2x80x9cpharmaceutically acceptable excipientxe2x80x9d means an excipient that is useful in preparing a pharmaceutical composition that is generally safe, non-toxic and neither biologically nor otherwise undesirable, and includes an excipient that is acceptable for veterinary use as well as human pharmaceutical use. xe2x80x9cA pharmaceutically acceptable excipientxe2x80x9d as used in the specification and claims includes both one and more than one such excipient.
A xe2x80x9cpharmaceutically acceptable saltxe2x80x9d of a compound means a salt that is pharmaceutically acceptable and that possesses the desired pharmacological activity of the parent compound. Such salts include:
(1) acid addition salts, formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or formed with organic acids such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethane-disulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic acid, 4-methylbicyclo[2.2.2]oct-2-ene-1-carboxylic acid, glucoheptonic acid, 4,4xe2x80x2-methylenebis-(3-hydroxy-2-ene-1-carboxylic acid), 3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, muconic acid, and the like; or
(2) salts formed when an acidic proton present in the parent compound either is replaced by a metal ion, e.g., an alkali metal ion, an alkaline earth ion, or an aluminum ion; or coordinates with an organic base such as ethanolamine, diethanolamine, triethanolamine, tromethamine, N-methylglucamine, and the like.
xe2x80x9cLeaving groupxe2x80x9d has the meaning conventionally associated with it in synthetic organic chemistry i.e., an atom or group capable of being displaced by a nucleophile and includes halogen, alkanesulfonyloxy, arenesulfonyloxy, ester, or amino such as chloro, bromo, iodo, mesyloxy, tosyloxy, trifluorosulfonyloxy, methoxy, N,O-dimethylhydroxylamino, and the like.
xe2x80x9cPro-drugsxe2x80x9d means any compound which releases an active parent drug according to Formula (I) in vivo when such prodrug is administered to a mammalian subject. Prodrugs of a compound of Formula (I) are prepared by modifying functional groups present in the compound of Formula (I) in such a way that the modifications may be cleaved in vivo to release the parent compound. Prodrugs include compounds of Formula (I) wherein a hydroxy, sulfhydryl or amino group in compound (I) is bonded to any group that may be cleaved in vivo to regenerate the free hydroxyl, amino, or sulfhydryl group, respectively. Unless indicated otherwise, the description of a particular compound in the specification and claims is intended to include the prodrugs of a compound of Formula (I). Examples of prodrugs include, but are not limited to esters (e.g., acetate, formate, and benzoate derivatives), carbamates (e.g., N,N-dimethylaminocarbonyl) of hydroxy functional groups in compounds of Formula (I), and the like.
xe2x80x9cTreatingxe2x80x9d or xe2x80x9ctreatmentxe2x80x9d of a disease includes:
(1) preventing the disease, i.e. causing the clinical symptoms of the disease not to develop in a mammal that may be exposed to or predisposed to the disease but does not yet experience or display symptoms of the disease,
(2) inhibiting the disease, i.e., arresting or reducing the development of the disease or its clinical symptoms, or
(3) relieving the disease, i.e., causing regression of the disease or its clinical symptoms.
A xe2x80x9ctherapeutically effective amountxe2x80x9d means the amount of a compound that, when administered to a mammal for treating a disease, is sufficient to effect such treatment for the disease. The xe2x80x9ctherapeutically effective amountxe2x80x9d will vary depending on the compound, the disease and its severity and the age, weight, etc., of the mammal to be treated.
The nomenclature used in this application is generally based on the IUPAC recommendations.
The pyrrolidine ring is numbered as follows: 
and the compounds of the invention are named as:
A compound of Formula (I) where Ar3 is 3,4-dichlorophenyl, alk2 is xe2x80x94CH2xe2x80x94, R1 is hydrogen, alk1 is xe2x80x94(CH2)2xe2x80x94, X is xe2x80x94CONHxe2x80x94, Y is xe2x80x94(CH2)2xe2x80x94 and Ar1 is pyrimidin-2-yl, Ar2 is 4-methoxyphenyl and is at the 5-position of the pyrimidine ring, is named N-[4-(3,4-dichlorobenzyl)pyrrolidin-2-ylethyl]-3-[5-(4-methoxyphenyl)pyrimidin-2-yl]propionamide.
A compound of Formula (I) where Ar3 is 3,4-dichlorophenyl, alk2 is xe2x80x94CH2xe2x80x94, R1 is methyl, alk1 is xe2x80x94(CH2)2xe2x80x94, X is xe2x80x94CONHxe2x80x94, Y is xe2x80x94SCH2xe2x80x94 and Ar1 is pyrimidin-2-yl, Ar2 is 3,4-methoxyphenyl and is at the 5-position of the pyrimidine ring, is named is named N-[4-(3,4-dichlorobenzyl)-1-methylpyrrolidin-2-ylethyl]-2-[5-(3,4-dimethoxyphenyl)pyrimidin-2-ylsulfanyl]acetamide.
A compound of Formula (I) where Ar3 is 3,4-dichlorophenyl, alk2 is xe2x80x94CH2xe2x80x94, R1 is methyl, alk1 is xe2x80x94(CH2)2xe2x80x94, X is xe2x80x94CONHxe2x80x94, Y is xe2x80x94OCH2xe2x80x94 and Ar1 is pyrimidin-2-yl, Ar2 is 3,4-methoxyphenyl and is at the 5-position of the pyrimidine ring, is named is named N-[4-(3,4-dichlorobenzyl)-1-methylpyrrolidin-2-ylethyl]-2-[5-(3,4-dimethoxyphenyl)pyrimidin-2-yloxy]acetamide.
A compound of Formula (I) where Ar3 is 3,4-dichlorophenyl, alk2 is xe2x80x94CH2xe2x80x94, R1 is methyl, alk1 is xe2x80x94(CH2)2xe2x80x94, X is xe2x80x94CONHxe2x80x94, Y is xe2x80x94NHCH2xe2x80x94 and Ar1 is pyrimidin-2-yl, Ar2 is 3,4-methoxyphenyl and is at the 5-position of the pyrimidine ring, is named is named N-[4-(3,4-dichlorobenzyl)-1-methylpyrrolidin-2-ylethyl]-2-[5-(3,4-dimethoxyphenyl)pyrimidin-2-ylamino]acetamide.
A compound of Formula (I) where Ar3 is 3,4-dichlorophenyl, alk2 is xe2x80x94CH2xe2x80x94, R1 is acetyl, alk1 is xe2x80x94(CH2)2xe2x80x94, X is xe2x80x94CONHxe2x80x94, Y is xe2x80x94SCH2xe2x80x94 and Ar1 is pyrimidin-2-yl, Ar2 is 3,4-methoxyphenyl and is at the 5-position of the pyrimidine ring, is named is named N-[1-acetyl-4-(3,4-dichlorobenzyl)pyrrolidin-2-ylethyl]-2-[5-(3,4-dimethoxyphenyl)pyrimidin-2-ylsulfanyl]-acetamide.
A compound of Formula (I) where Ar3 is 3,4-dichlorophenyl, alk2 is xe2x80x94CH2xe2x80x94-, R1 is hydrogen, alk1 is xe2x80x94(CH2)xe2x80x94, X is xe2x80x94CONHxe2x80x94, Y is xe2x80x94CH2NHxe2x80x94, Ar1 is pyrimidinyl, and Ar is 4-methoxyphenyl and is at the 5-position of the pyrimidine ring, is named 1-[4-(3,4-dichlorobenzyl)pyrrolidin-2-ylmethyl]-3-(4-methoxyphenylpyrimidin-2-ylmethyl)urea.
1. Representative compounds of Formula (I):
While the broadest definition of this invention is set forth in the Summary of the Invention, certain compounds of Formula (I) are preferred.
(A) A preferred group of compounds of Formula (I) is represented by Formula (Ia): 
wherein:
R1 is hydrogen, alkyl, acyl, heteroalkyl, xe2x80x94CONR3R4 (where R3 and R4 are independently hydrogen or alkyl), xe2x80x94COOR5 (where R5 is hydrogen, alkyl or heteroalkyl), or xe2x80x94SO2R6 where R6 is alkyl;
alk2 is an alkylene chain of 1 to 6 carbon atoms;
X is xe2x80x94NHCOxe2x80x94 or xe2x80x94CONHxe2x80x94;
Y is xe2x80x94Oxe2x80x94(CH2)xe2x80x94, xe2x80x94Oxe2x80x94(CH2)2xe2x80x94, xe2x80x94Oxe2x80x94(CHCH3)xe2x80x94, xe2x80x94NRbxe2x80x94(CH2)xe2x80x94, xe2x80x94NRbxe2x80x94(CH2)2xe2x80x94, xe2x80x94NRbxe2x80x94(CHCH3)xe2x80x94 [where Rb is hydrogen, alkyl, acyl, xe2x80x94CONR7R8 (where R7 and R8 are independently hydrogen or alkyl), xe2x80x94COOR9 (where R9 is hydrogen, alkyl or heteroalkyl), aryl, or aralkyl)], xe2x80x94S(O)nxe2x80x94(CH2)xe2x80x94, xe2x80x94S(O)nxe2x80x94(CH2)2xe2x80x94, or xe2x80x94S(O)nxe2x80x94(CHCH3)xe2x80x94 where n is 0 to 2;
Ar1 is a heteroaryl group or phenyl group wherein the heteroaryl or phenyl group is substituted, in addition to the Ar2 group, with a substituent selected from the group consisting of hydrogen, halo, alkyl, alkoxy, nitro, amido, aminosulfonyl and sulfonylamino;
Ar2 is aryl;
alk2 is an alkylene chain of 1 to 6 carbon atoms wherein one of the carbon atoms is optionally replaced by xe2x80x94COxe2x80x94, xe2x80x94NRcxe2x80x94 [where Rc is hydrogen, alkyl, acyl, xe2x80x94CONR10R11 (where R10 and R11 are independently hydrogen or alkyl), xe2x80x94COOR12 (where R12 is hydrogen, alkyl or heteroalkyl), aryl, or aralkyl)] or xe2x80x94S(O)n1xe2x80x94 wherein n1 is 0 to 2;
Ar3 is cycloalkyl, aryl or heteroaryl; or a pharmaceutically acceptable salts thereof.
Preferably, R1 is hydrogen, alkyl, acyl, or xe2x80x94SO2Ra where Ra is alkyl. More preferably, R1 is hydrogen, methyl, ethyl, acetyl, trifluoroacetyl, xe2x80x94COCH2CO2H, xe2x80x94COCH2CO2Rxe2x80x2 where Rxe2x80x2 is alkyl, or xe2x80x94SO2CH3. Even more preferably, R1 is hydrogen, methyl, acetyl, xe2x80x94COCH2CO2H, xe2x80x94COCH2CO2CH3, xe2x80x94CO2-tert-butyl.
Preferably, alk1 is an alkylene chain of 1 to 3 carbon atoms; more preferably methyl, ethyl or n-propyl, even more preferably methyl or ethyl.
Preferably, X is xe2x80x94CONHxe2x80x94.
Preferably, Y is xe2x80x94SCH2xe2x80x94, xe2x80x94OCH2xe2x80x94 or xe2x80x94NHCH2xe2x80x94. More preferably, Y is xe2x80x94SCH2xe2x80x94 or xe2x80x94OCH2xe2x80x94.
Preferably, Ar1 is a heteroaryl group. More preferably Ar1 is pyridyl or pyrimidinyl. More preferably Ar1 is pyridin-2-yl or pyrimidin-2-yl. Even more preferably pyrimidin-2-yl.
Preferably, Ar2 is aryl optionally substituted with one or two substituents selected from the group consisting of alkoxy, hydroxy, or halo. More preferably, Ar2 is phenyl or 3,4-dimethoxyphenyl and is at the 5-position of the pyrimidin-2-yl or pyridin-2-yl ring.
Preferably, alk2 is an alkylene group of 1 to 3 carbon atoms, more preferably xe2x80x94CH2xe2x80x94.
Preferably, Ar3 is aryl. More preferably, Ar3 is phenyl optionally substituted with 1 or 2 halo groups. Even more preferably, Ar3 is 3,4-dichlorophenyl.
Preferably, X is xe2x80x94CONHxe2x80x94 and Y is xe2x80x94SCH2xe2x80x94 or xe2x80x94OCH2xe2x80x94.
Preferably, X is xe2x80x94CONHxe2x80x94, Y is xe2x80x94SCH2xe2x80x94 or xe2x80x94OCH2xe2x80x94 and Ar1 is pyridyl or pyrimidinyl. More preferably Ar1 is pyridin-2-yl or pyrimidin-2-yl. Even more preferably pyrimidin-2-yl.
(B) Another preferred compounds of Formula (I) are represented by Formula (Ib): 
wherein:
R1 is hydrogen, alkyl, acyl, heteroalkyl, xe2x80x94CONR3R4 (where R3 and R4 are independently hydrogen or alkyl), xe2x80x94COOR5 (where R5 is hydrogen, alkyl or heteroalkyl), or xe2x80x94SO2R6 where R6 is alkyl;
alk1 is an alkylene chain of 1 to 6 carbon atoms;
X is xe2x80x94NHCOxe2x80x94 or xe2x80x94CONHxe2x80x94;
Y is:
(i) xe2x80x94(CH2)xe2x80x94, xe2x80x94(CH2)2xe2x80x94, xe2x80x94(CH2)3xe2x80x94, xe2x80x94(CHCH3)xe2x80x94, xe2x80x94(CHCH3)xe2x80x94(CH2)xe2x80x94, or xe2x80x94(CH2)xe2x80x94(CHCH3)xe2x80x94; or
(ii) xe2x80x94(CH2)xe2x80x94Oxe2x80x94, xe2x80x94(CH2)2xe2x80x94Oxe2x80x94, xe2x80x94(CHCH3)xe2x80x94Oxe2x80x94, xe2x80x94(CH2)xe2x80x94NRbxe2x80x94, xe2x80x94(CH2)2xe2x80x94NRbxe2x80x94, or xe2x80x94(CHCH3)xe2x80x94NRbxe2x80x94 [where Rb is hydrogen, alkyl, acyl, xe2x80x94CONR7R8 (where R7 and R8 are independently hydrogen or alkyl), xe2x80x94COOR9 (where R9 is hydrogen, alkyl or heteroalkyl), aryl, or aralkyl)] when X is xe2x80x94CONHxe2x80x94;
Ar1 is a heteroaryl group or phenyl group wherein the heteroaryl or phenyl group is substituted, in addition to the Ar2 group, with a substituent selected from the group consisting of hydrogen, halo, alkyl, alkoxy, nitro, amido, aminosulfonyl and sulfonylamino;
Ar2 is aryl;
alk2 is an alkylene chain of 1 to 6 carbon atoms wherein one of the carbon atoms is optionally replaced by xe2x80x94COxe2x80x94, xe2x80x94NRcxe2x80x94[where Rc is hydrogen, alkyl, acyl, xe2x80x94CONR10R11 (where R10 and R11 are independently hydrogen or alkyl), xe2x80x94COOR12 (where R12 is hydrogen, alkyl or heteroalkyl), aryl, or aralkyl)] or xe2x80x94S(O)n1xe2x80x94 wherein n1 is 0 to 2;
Ar3 is cycloalkyl, aryl or heteroaryl; or a pharmaceutically acceptable salts thereof.
Preferably, R1 is hydrogen, alkyl, acyl, or xe2x80x94SO2Ra where Ra is alkyl. More preferably, R1 is hydrogen, methyl, ethyl, acetyl, trifluoroacetyl, xe2x80x94COCH2CO2H, xe2x80x94COCH2CO2Rxe2x80x2 where Rxe2x80x2 is alkyl or xe2x80x94SO2CH3. Even more preferably, R1 is hydrogen, methyl, acetyl, xe2x80x94COCH2CO2H, xe2x80x94COCH2CO2CH3, xe2x80x94CO2-tert-butyl.
Preferably, alk1 is an alkylene chain of 1 to 3 carbon atoms; more preferably methyl, ethyl or n-propyl, even more preferably methyl or ethyl.
Preferably, X is xe2x80x94CONHxe2x80x94.
Preferably, Y is xe2x80x94CH2xe2x80x94 or xe2x80x94(CH2)2xe2x80x94.
Preferably, Y is xe2x80x94(CH2)xe2x80x94NRbxe2x80x94 or xe2x80x94(CH2)2xe2x80x94NRbxe2x80x94 [where Rb is hydrogen, alkyl, acyl, xe2x80x94CONR7R8 (where R7 and R8 are independently hydrogen or alkyl), xe2x80x94COOR9 (where R9 is hydrogen, alkyl or heteroalkyl), aryl, or aralkyl)] when X is xe2x80x94CONHxe2x80x94;
Preferably, Ar1 is a heteroaryl group. More preferably pyridyl or pyrimidinyl. More preferably Ar1 is pyridin-2-yl or pyrimidin-2-yl. Even more preferably pyrimidin-2-yl.
Preferably, Ar2 is aryl optionally substituted with one or two substituents selected from the group consisting of alkoxy, hydroxy, or halo. More preferably, Ar2 is phenyl or 3,4-dimethoxyphenyl and is at the 5-position of the pyrimidin-2-yl or pyridin-2-yl ring.
Preferably, alk2 is an alkylene group of 1 to 3 carbon atoms, more preferably or xe2x80x94CH2xe2x80x94 or xe2x80x94(CH2)2xe2x80x94.
Preferably, Ar3 is aryl. More preferably, Ar3 is phenyl optionally substituted with 1 or 2 halo groups. Even more preferably, Ar3 is 3,4-dichlorophenyl.
Preferably, X is xe2x80x94CONHxe2x80x94 and Y is xe2x80x94(CH2)2xe2x80x94.
Preferably, X is xe2x80x94CONHxe2x80x94 and Y is xe2x80x94(CH2)2xe2x80x94NHxe2x80x94 or xe2x80x94CH2xe2x80x94NHxe2x80x94.
Preferably, X is xe2x80x94CONHxe2x80x94, Y is xe2x80x94(CH2)2xe2x80x94 and Ar1 is pyridyl or pyrimidinyl. More preferably Ar1 is pyridin-2-yl or pyrimidin-2-yl. Even more preferably pyrimidin-2-yl.
The compounds of the present invention can be prepared in a number of ways known to one skilled in the art. Preferred methods include, but are not limited to, the general synthetic procedures described below.
The starting materials and reagents used in preparing these compounds are either available from commercial suppliers such as Aldrich Chemical Co., (Milwaukee, Wis., U.S.A.), Bachem (Torrance, Calif., U.S.A.), Emka-Chemie, or Sigma (St. Louis, Mo., U.S.A.), Maybridge (Dist: Ryan Scientific, P.O. Box 6496, Columbia, S.C. 92960), Bionet Research Ltd., (Cornwall PL32 9QZ, UK), Menai Organics Ltd., (Gwynedd, N. Wales, UK), Butt Park Ltd., (Dist. Interchim, Montlucon Cedex, France) or are prepared by methods known to those skilled in the art following procedures set forth in references such as Fieser and Fieser""s Reagents for Organic Synthesis, Volumes 1-17 (John Wiley and Sons, 1991); Rodd""s Chemistry of Carbon Compounds, Volumes 1-5 and Supplementals (Elsevier Science Publishers, 1989), Organic Reactions, Volumes 1-40 (John Wiley and Sons, 1991), March""s Advanced Organic Chemistry, (John Wiley and Sons, 1992), and Larock""s Comprehensive Organic Transformations (VCH Publishers Inc., 1989). These schemes are merely illustrative of some methods by which the compounds of this invention can be synthesized, and various modifications to these schemes can be made and will be suggested to one skilled in the art having referred to this disclosure.
The starting materials and the intermediates of the reaction may be isolated and purified if desired using conventional techniques, including but not limited to filtration, distillation, crystallization, chromatography, and the like. Such materials may be characterized using conventional means, including physical constants and spectral data.
Compounds of Formula (I) where X is xe2x80x94CONHxe2x80x94, alk1 is xe2x80x94CH2xe2x80x94, the other groups are as defined in the Summary of the Invention and the stereochemistry at C2 and C4 carbon atoms of the pyrrolidine ring is (2S,4R) can be prepared as illustrated in described in Scheme I below. 
Treatment of ethyl (S)-2-pyrrolidone-5-carboxylate 1 with di-tert-butyldicarbonate provides ethyl (S)-1-tert-butoxycarbonyl-2-pyrrolidone-5-carboxylate 2. The reaction is carried out in an inert organic solvent such as methylene chloride, chloroform, ether and the like, in the presence of an organic amine such as triethylamine and dimethylaminopyridine at room temperature. It will be recognized by a person skilled in the art that other suitable nitrogen protecting groups such a benzyloxycarbonyl can be used.
Treatment of 2 with an aralkyl halide/heteroaralkyl halide of formula Ar3-alk2-LG where Ar3 and alk2 are as defined in the Summary of the Invention and LG is suitable leaving group such as halo, tosylate, mesylate, triflate, and the like, provides a 4-substituted ethyl (S)-1-tert-butoxycarbonyl-2-pyrrolidone-5-carboxylate 3. The reaction is carried out in the presence of a strong base such as LiHDMS, in an ethereal solution such as tetrahydrofuran, diethyl ether and the like. The reaction is initially carried out at approximately xe2x88x9278xc2x0 C. and then warmed to ambient temperature. Aralkyl halide/heteroaralkyl halide of formula Ar3-alk2-LG are commercially available or they can be prepared by methods skilled in the art. For example, benzyl chloride, 3,4-dichlorobenzyl bromide, and 3-chlorobenzyl chloride are commercially available. Others can be prepared from commercially available alcohols such as benzylalcohol, 2-phenylethanol, 3-phenylpropanol by treating them with a halogenating agent such as PBr3 POCl3 and the like. Alternatively, the alcohols can be converted to mesyl, tosyl, or triflate derivatives by methods well known in the art and can be used in the above reaction in lieu of the alkyl halides.
Reduction of the ester and the amido groups in compound 3 with a suitable reducing agent such as borane in ethereal solution such as tetrahydrofuran at around 40xc2x0 C. provides the corresponding (2S,4R)-4-(aralkyl or heteroaralkyl)-2-hydroxymethyl-1-tert-butoxycarbonylpyrrolidine of formula 4. The hydroxy group in 4 is converted to a suitable leaving group such as mesylate, tosylate, and the like, by methods well known in the art. The reaction is carried out by treating 4 with methanesulfonyl chloride or p-toluenesulfonyl chloride respectively, in the presence of a base such as triethylamine, pyridine, and the like, and in an inert solvent such as methylene chloride, and the like.
Displacement of the mesylate/tosylate group in compound 5 with an azide ion, followed by reduction of the azido group in the resulting (2S,4R)-4-(aralkyl or heteroaralkyl)-2-azidomethyl-1-tert-butoxycarbonylpyrrolidine of formula 6 then provides a (2S,4R)-4-(aralkyl or heteroaralkyl)-2-aminomethyl-1-tert-butoxycarbonylpyrrolidine of formula 7. The displacement of the mesylate group occurs upon heating 5 with sodium azide in a polar organic solvent such as dimethylformamide.
Reduction of the azido group in 6 to the amino group is carried out under catalytic hydrogenation reaction conditions utilizing a suitable catalyst such as platinum oxide. The reaction is carried out in ethyl acetate at atmospheric pressure and ambient temperature.
Compound 7 is then converted to a compound of Formula (I) where X is xe2x80x94CONHxe2x80x94 group by treating 7 with an acid of formula 8 where Ar1, Ar2, and Y are as defined in the Summary of the Invention. The reaction is carried out in the presence of a coupling agent such as 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide, diethylazacarbodimide (DEAD), and the like, and optionally in the presence of a catalyst such as 1-hydroxybenzotriazole hydrate. The reaction is carried out in solvents such as methylene chloride, tetrahydrofuran, and the like and at ambient temperature. Alternatively, the coupling reaction can be carried out by converting 8 to an acid halide such as acid chloride followed by reaction with 7 in the presence of a base such as triethylamine, pyridine, and the like.
Acids of formula 8 are commercially available or they can be prepared by methods well known in the art. For example, 2-(5-methyl-2-phenyloxazol-4-yl)acetic acid, 2-(3-methyl-2-N-phenylpyrazol-4-yl)acetic acid, 2-(2-pyrazin-2-ylthiazol-4-yl)acetic acid, 2-[2-(pyridin-2-yl)-6-trifluoromethylpyrimidin-4-ylsulfanyl]acetic acid, 2-[6-(4-chlorophenyl)pyrimidin-2-ylsulfanyl]acetic acid, 2-(3-phenylpyrazol-1-yl)acetic acid, and 2-methyl-2-(4-thiophenoylphenyl)-acetic acid are commercially available.
Others can be prepared by methods well known in the art. For example, 3-[4-(4-methoxyphenyl)pyrimidin-2-yl]propanoic acid can be prepared by adding a solution of sodium ethoxide (21% wt/vol in ethanol, 10 mL, 30 mmol, 3 equiv.) to a suspension of 2-(4-methoxyphenyl)trimethinium perchlorate (3.3 g, 9.8 mmol) [see, Jutz, C.; Kirchlechner, R.; Seidel, H. Chem. Ber. 102, 2301, (1969)] and 4-amidinobutanoic acid mono HCl (1.5 g, 9.8 mmol) [see, McElvain, S. M.; Schroeder, J. P. J. Am. Chem. Soc., 71, 40, (1949)] in absolute ethanol (40 mL) and heating the reaction mixture at reflux for 12 h. The suspension is concentrated, diluted with water, and washed with ether. The aqueous phase is then made acidic with citric acid (10 g). The precipitates are filtered, washed with water and ether, and dried under high vacuum to yield 3-[4-(4-methoxyphenyl)-pyrimidin-2-yl]propanoic acid.
3-[5-(4-nitrophenyl)pyrimidin-2-yl]-propanoic acid is prepared as follows: Phosphorus oxychloride (83 mL, 0.79 mol) is added slowly to cold, dry dimethylformamide (100 mL) under N2 at such a rate that the temperature does not rise above 5xc2x0 C. After addition is complete, 4-nitrophenylacetic acid (48 g, 0.26 mol) is added in one portion and the reaction mixture is heated to 85xc2x0 C. over 1 h. The reaction mixture is cooled, then poured over ice. Solid sodium perchlorate monohydrate (37 g, 0.26 mol) is added to initiate precipitation of the product as the perchlorate salt. Filtration of the solid, followed by washings with cold water, methanol and ether, provides 2-(4-nitrophenyl)trimethinium perchlorate.
A solution of sodium ethoxide (21% wt/vol, in ethanol, 60 mL, 180 mmol, 3 equiv.) is added in one portion to a suspension of 2-(4-nitrophenyl)trimethinium perchlorate (20.8 g, 60 mmol) and 4-amidinopropionic acid mono hydrochloride salt (9.1 g, 60 mmol) in ethanol (300 mL). The suspension is heated at room temperature overnight. The resulting suspension is filtered, washed with ethanol, cold HCl, water and ether, then dried under high vacuum to give 3-[5-(4-nitrophenyl)pyrimidin-2-yl]-propanoic acid which can be hydrogenated under standard catalytic hydrogenation conditions (i.e., using Pd/C catalytst in methanol solvent at atmospheric pressure) to provide 3-{5-(4-aminophenyl)pyrimidin-2-yl]propionic acid.
2-[5-(4-Methoxyphenyl)pyrimidin-2-ylamino]-acetic acid (150 mg) is prepared by adding ethanolic solution of sodium ethoxide (2.7 M, 3.8 mL, 10 mmol, 2.9 equiv.) to a suspension of 2-(4-methoxyphenyl)trimethinium perchlorate salt (1.1 g, 3.4 mmol) and guanidineacetic acid (0.48 g, 4.0 mmol, 1.2 equiv.) in dehydrated ethanol (20 mL). The reaction mixture is stirred at room temperature for 30 min., then at reflux temperature for 3 h. After cooling, the sodium salt is filtered, and the cake is dissolved in 20 mL of water then acidified with 1 M hydrochloric acid. The aqueous layer is extracted with ethyl acetate and the combined organic phases are washed with brine, and dried over sodium sulfate. Removal of the solvent under vacuum affords a solid which contained xcx9c1:1 mixture of regioisomers. The two components are separated using reversed-phase chromatography to give 2-[5-(4-methoxyphenyl)pyrimidin-2-ylamino]acetic acid and the regioisomer.
2-(5-Phenylpyrimidin-2-yloxy)acetic acid and derivatives thereof can be prepared by reacting 5-bromo-2-chloropyrimidine (prepared as described in PCT application Publication No WO 00/31032 the disclosure of which is incorporated herein in it""s entirety) with methyl glycolate to give methyl 5-bromopyrimidin-2-yloxyacetate. Coupling of methyl 5-bromopyrimidin-2-yloxyacetate with phenylboronic acid under the reaction conditions described Example 8, step 5 of WO 00/31032, followed by basic hydrolysis of the ester group provides 2-(5-phenylpyrimidin-2-yloxy)acetic acid.
Deprotection of the BOC group then provides a compound of Formula (I) where R1 is hydrogen. The deprotection is carried out under acidic hydrolysis reaction conditions. Suitable acids are trifluoroacetic acid, hydrochloric acid, and the like.
A compound of Formula (I) where R1 is hydrogen can then be converted to other compounds of Formula (I) where R1 is other than hydrogen by methods well known in the art.
A compound of Formula (I) where R1 is hydrogen can be treated with an acyl halide or sulfonyl halide in the presence of a non-nucleophilic base such as triethylamine, pyridine, and the like and in a suitable organic solvent such as methylene chloride, tetrahydrofuran, and the like to provide a corresponding compound of Formula (I) where R1 is acyl. Acyl halides such as acetyl chloride, propionyl chloride, trifluoroacetyl chloride, and monomethoxy malonyl chloride, are commercially available. Sulfonyl halides such as methanesulfonyl chloride are commercially available.
A compound of Formula (I) having an alkoxy substituent for example on the Ar1 or Ar3 group can be converted to a corresponding compound of Formula (I) with a hydroxy group by dealkylation of the alkoxy group under conditions well known in the art. Similarly, a compound of Formula (I) having a nitro substituent for example on the Ar1 or Ar3 group can be converted to a corresponding compound of Formula (I) with an amino group under standard catalytic hydrogenation reaction conditions.
Additionally, utilizing ethyl (R)-2-pyrrolidone-5-carboxylate as the starting material in place of ethyl (S)-2-pyrrolidone-5-carboxylate 1, provides compounds of Formula (I) having (2R,4S) stereochemistry at the pyrrolidine ring.
Compounds of Formula (I) where X is xe2x80x94CONHxe2x80x94, alk1 is xe2x80x94(CH2)2xe2x80x94, the other groups are as defined in the Summary of the Invention and the stereochemistry at the C2 and C4 carbon atoms of the pyrrolidine ring is (2S,4R) can be prepared as illustrated and described in Scheme II below. 
A compound of Formula (I) where X is xe2x80x94CONHxe2x80x94 and alk1 is xe2x80x94(CH2)2xe2x80x94 and the other groups are as defined in the Summary of the Invention can be prepared from a compound of formula 5 by first converting it to a cyano derivative of formula 10 by reacting it with sodium or potassium cyanide in dimethyl sulfoxide between 70-90xc2x0 C. Reduction of the cyano group with a suitable reducing agent such as diborane in tetrahydrofuran then provides aminoethyl derivative of formula 11. Compound 11 is then converted to a compound of Formula (I) where X is xe2x80x94CONHxe2x80x94 as described in Scheme I above. Here too, substituting ethyl (R)-2-pyrrolidone-5-carboxylate as the starting material in place of ethyl (S)-2-pyrrolidone-5-carboxylate provides a compound of Formula (I) having (2R, 4S) stereochemistry at the pyrrolidine ring.
Compounds of Formula (I) where X is xe2x80x94CONHxe2x80x94, R1 is alkyl, alk1 is xe2x80x94(CH2)xe2x80x94, the other groups are as defined in the Summary of the Invention and the stereochemistry at C2 and C4 carbon atoms in the pyrrolidine ring is either (2S,4S) or (2S,4R) can be are prepared as illustrated and described in Scheme III below. 
Removal of the tert-butoxycarbonyl group in compound 3 in the presence of a strong base such as sodium hydride above provides a compound of formula 12. Alkylation of 12 with an alkyl halide of formula R1LG where LG is chloro, bromo or iodo provides a mixture of diasteromers of formula 13a and 13b. The diastereomers can be separated, if desired, by column chromatography as described in Example 4 below. Treatment of 13a or 13b with ammonia in methanol at room temperature provides the corresponding 2-amido-5-oxopyrrolidine derivative of formula 14a or 14b respectively.
Reduction of the 2-amido group in 14a or 14b provides the corresponding 2-aminomethylpyrrolidine derivative of formula 15a or 15b respectively which is then converted to a compound of Formula (I) as described in detail in Scheme I above. The reduction of the amido group is carried out by heating 14a or 14b with diborane in tetrahydrofuran.
Substituting ethyl (R)-2-pyrrolidone-5-carboxylate as the starting material in place of ethyl (S)-2-pyrrolidone-5-carboxylate, the enantiomers of 15a and 15b are obtained as products.
Alternatively, compounds of Formula (I) where the pyrrolidine ring has (2S,4S) stereochemistry i.e, the groups at C-2 and C-4 position of the pyrrolidine ring are syn to each other can be prepared by heating compound 3 in dimethylfomamide in the presence of potassium cyanide as described in Esquerra, J., et al, Tetrahedron, 49, 8665 (1993). This reaction causes racemization at the C-4 carbon in 3 thus providing compounds of formula 3 wherein the xe2x80x94CO2Et and the -alk2-Ar3 groups are either syn or trans to each other. These diasteromers can be separated and then converted to a compound of Formula (I) as described above.
Compounds of Formula (I) where X is xe2x80x94CONHxe2x80x94, R1 is methyl, alk1 is xe2x80x94(CH2)2xe2x80x94, the other groups are as defined in the Summary of the Invention and the stereochemistry at the C2 and C4 carbons atoms in the pyrrolidine ring is (2S,4R) can be prepared as illustrated and described in Scheme IV below. 
Prolonged heating of compound 3 with excess diborane in tetrahydrofuran, followed by heating with hydrochloric acid in methanol provides an N-methyl-2-hydroxymethylpyrrolidine derivative of formula 16. Compound 16 is then converted to a compound of Formula (I) where X is xe2x80x94CONHxe2x80x94, alk1 is xe2x80x94(CH2)2xe2x80x94, the other groups are as defined in the Summary of the Invention and the stereochemistry at the pyrrolidine ring is (2S,4R) as described in Scheme II above.
The compounds of the invention are CCR-3 receptor antagonists and inhibit eosinophil recruitment by CCR-3 chemokines such as RANTES, eotaxin, MCP-2, MCP-3 and MCP-4. Compounds of this invention and compositions containing them are useful in the treatment of eosiniphil-induced diseases such as inflammatory or allergic diseases and including respiratory allergic diseases such as asthma, allergic rhinitis, hypersensitivity lung diseases, hypersensitivity pneumonitis, eosinophilic pneumonias (e.g., chronic eosinophilic pneumonia); inflammatory bowel diseases (e.g., Crohn""s disease and ulcerative colitis); and psoriasis and inflammatory dermatoses such as dermatitis and eczema.
Additionally, it has recently been discovered that the CCR-3 receptor plays a role in the pathogenesis of Acquired Immune Deficiency Syndrome (AIDS). Accordingly, the compounds of this invention and compositions containing them are also useful in the treatment of AIDS.
The CCR-3 antagonistic activity of the compounds of this invention was measured by in vitro assays such as ligand binding and chemotaxis assays as described in more detail in Examples 9, 10 and 11. In vivo activity was assayed in the Ovalbumin induced Asthma in Balb/c Mice Model as described in more detail in Example 12.
In general, the compounds of this invention will be administered in a therapeutically effective amount by any of the accepted modes of administration for agents that serve similar utilities. The actual amount of the compound of this invention, i.e., the active ingredient, will depend upon numerous factors such as the severity of the disease to be treated, the age and relative health of the subject, the potency of the compound used, the route and form of administration, and other factors.
Therapeutically effective amounts of compounds of Formula (I) may range from approximately 0.01-20 mg per kilogram body weight of the recipient per day; preferably about 0.1-10 mg/kg/day. Thus, for administration to a 70 kg person, the dosage range would most preferably be about 7 mg to 0.7 g per day.
In general, compounds of this invention will be administered as pharmaceutical compositions by any one of the following routes: oral, inhalation (e.g., intranasal or oral inhalation) or parenteral (e.g., intramuscular, intravenous or subcutaneous) administration. A preferred manner of administration is oral using a convenient daily dosage regimen which can be adjusted according to the degree of affliction. Compositions can take the form of tablets, pills, capsules, semisolids, powders, sustained release formulations, solutions, suspensions, liposomes, elixirs, or any other appropriate compositions. Another preferred manner for administering compounds of this invention is inhalation. This is an effective means for delivering a therapeutic agent directly to the respiratory tract for the treatment of diseases such as asthma and other similar or related respiratory tract disorders (see U.S. Pat. No. 5,607,915).
The choice of formulation depends on various factors such as the mode of drug administration and the bioavailability of the drug substance. For delivery via inhalation the compound can be formulated as liquid solutions or suspensions, aerosol propellants or dry powder and loaded into a suitable dispenser for administration. There are three types of pharmaceutical inhalation devicesxe2x80x94nebulizer inhalers, metered-dose inhalers (MDI) and dry powder inhalers (DPI). Nebulizer devices produce a stream of high velocity air that causes the therapeutic agents (which has been formulated in a liquid form) to spray as a mist which is carried into the patient""s respiratory tract. MDI""s typically have the formulation packaged with a compressed gas. Upon actuation, the device discharges a measured amount of therapeutic agent by compressed gas, thus affording a reliable method of administering a set amount of agent. DPI""s administer therapeutic agents in the form of a free flowing powder that can be dispersed in the patient""s inspiratory air-stream during breathing by the device. In order to achieve a free flowing powder, the therapeutic agent is formulated with an excipient, such as lactose. A measured amount of the therapeutic is stored in a capsule form and is dispensed to the patient with each actuation. Recently, pharmaceutical formulations have been developed especially for drugs that show poor bioavailability based upon the principle that bioavailability can be increased by increasing the surface area i.e., decreasing particle size. For example, U.S. Pat. No. 4,107,288 describes a pharmaceutical formulation having particles in the size range from 10 to 1,000 nm in which the active material is supported on a crosslinked matrix of macromolecules. U.S. Pat. No. 5,145,684 describes the production of a pharmaceutical formulation in which the drug substance is pulverized to nanoparticles (average particle size of 400 nm) in the presence of a surface modifier and then dispersed in a liquid medium to give a pharmaceutical formulation that exhibits remarkably high bioavailability.
The compositions are comprised of in general, a compound of Formula (I) in combination with at least one pharmaceutically acceptable excipient. Acceptable excipients are non-toxic, aid administration, and do not adversely affect the therapeutic benefit of the compound of Formula (I). Such excipient may be any solid, liquid, semi-solid or, in the case of an aerosol composition, gaseous excipient that is generally available to one of skill in the art.
Solid pharmaceutical excipients include starch, cellulose, talc, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, magnesium stearate, sodium stearate, glycerol monostearate, sodium chloride, dried skim milk and the like. Liquid and semisolid excipients may be selected from glycerol, propylene glycol, water, ethanol and various oils, including those of petroleum, animal, vegetable or synthetic origin, e.g., peanut oil, soybean oil, mineral oil, sesame oil, etc. Preferred liquid carriers, particularly for injectable solutions, include water, saline, aqueous dextrose, and glycols.
Compressed gases may be used to disperse a compound of this invention in aerosol form. Inert gases suitable for this purpose are nitrogen, carbon dioxide, etc.
For liposomal formulations of the drug for parenteral or oral delivery the drug and the lipids are dissolved in a suitable organic solvent e.g. tert-butanol, cyclohexane (1% ethanol). The solution is lypholized and the lipid mixture is suspended in an aqueous buffer an allowed to form a liposome. If necessary, the liposome size can be reduced by sonification. (see., Frank Szoka, Jr. and Demetrios Papahadjopoulos, xe2x80x9cComparative Properties and Methods of Preparation of Lipid Vesicles (Liposomes)xe2x80x9d, Ann. Rev. Biophys. Bioeng., 9:467-508 (1980), and D. D. Lasic, xe2x80x9cNovel Applications of Liposomesxe2x80x9d, Trends in Biotech., 16:467-608, (1998))
Other suitable pharmaceutical excipients and their formulations are described in Remington""s Pharmaceutical Sciences, edited by E. W. Martin (Mack Publishing Company, 18th ed., 1990).
The level of the compound in a formulation can vary within the full range employed by those skilled in the art. Typically, the formulation will contain, on a weight percent (wt %) basis, from about 0.01-99.99 wt % of a compound of Formula (I) based on the total formulation, with the balance being one or more suitable pharmaceutical excipients. Preferably, the compound is present at a level of about 1-80 wt %. Representative pharmaceutical formulations containing a compound of Formula (I) are described in Example 8.